CN106243182B - Enoxolone-hydrogen sulfide donor reagent derivatives and its synthetic method and application - Google Patents
Enoxolone-hydrogen sulfide donor reagent derivatives and its synthetic method and application Download PDFInfo
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- CN106243182B CN106243182B CN201610621147.1A CN201610621147A CN106243182B CN 106243182 B CN106243182 B CN 106243182B CN 201610621147 A CN201610621147 A CN 201610621147A CN 106243182 B CN106243182 B CN 106243182B
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- Prior art keywords
- compound
- hydrogen sulfide
- donor reagent
- sulfide donor
- synthesis method
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- 229910000037 hydrogen sulfide Inorganic materials 0.000 title claims abstract description 27
- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 24
- 238000010189 synthetic method Methods 0.000 title description 6
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- 229940125904 compound 1 Drugs 0.000 claims abstract description 21
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 19
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 19
- 238000001308 synthesis method Methods 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000002798 polar solvent Substances 0.000 claims abstract description 15
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960003720 enoxolone Drugs 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 11
- MPDGHEJMBKOTSU-WFJWTYAKSA-N (2s,4as,6as,6br,10s,12as)-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid Chemical class C12C(=O)C=C3C4C[C@@](C)(C(O)=O)CC[C@]4(C)CC[C@@]3(C)[C@]1(C)CCC1[C@]2(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-WFJWTYAKSA-N 0.000 claims abstract description 10
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种甘草次酸‑硫化氢供体试剂衍生物及其合成方法和应用。该衍生物的合成方法为：取甘草次酸、α,ω‑二溴烷烃和碱在非质子极性溶剂中反应，得到化合物1；取化合物1、硫化氢供体试剂和碱在非质子极性溶剂中反应，得到目标物粗品；其中，反应在加热或不加热的条件下进行。合成得到衍生物中的大部分化合物对慢性骨髓性白血病细胞K562具有一定的抑制活性，有望用于相应的抗肿瘤药物及治疗慢性骨髓性白血病的药物的制备。所述合成得到的衍生物具有下述通式(I)所示结构：其中，n为2～8；R为或 The invention discloses a derivative of glycyrrhetinic acid-hydrogen sulfide donor reagent, its synthesis method and application. The synthesis method of the derivative is as follows: react glycyrrhetinic acid, α,ω-dibromoalkane and base in an aprotic polar solvent to obtain compound 1; take compound 1, hydrogen sulfide donor reagent and base in an aprotic polar solvent React in a neutral solvent to obtain the crude product of the target; wherein, the reaction is carried out with or without heating. Most of the compounds in the synthesized derivatives have certain inhibitory activity on chronic myelogenous leukemia cell K562, and are expected to be used in the preparation of corresponding antineoplastic drugs and drugs for treating chronic myelogenous leukemia. The derivative obtained by the synthesis has a structure shown in the following general formula (I): Among them, n is 2-8; R is or
Description
技术领域technical field
本发明涉及医药技术领域，具体涉及一种甘草次酸-硫化氢供体试剂衍生物及其合成方法和应用。The invention relates to the technical field of medicine, in particular to a glycyrrhetinic acid-hydrogen sulfide donor reagent derivative and its synthesis method and application.
背景技术Background technique
硫化氢是相继于CO和NO之后的一个新的生物活性气体分子，是支持生命的重要角色，在生命活动中具有不可替代的生理调节作用，控制多种细胞内信号传导过程并发挥积极的调节作用。目前关于硫化氢的潜在治疗性应用主要集中在神经、心血管系统，如治疗高血压、治疗心脏缺血性疾病，治疗动脉粥样硬化，与非甾体类抗炎药联用，用于降低代谢、防止低氧性损伤等。Hydrogen sulfide is a new biologically active gas molecule following CO and NO. It is an important role in supporting life. It has an irreplaceable physiological regulatory role in life activities, controls a variety of intracellular signal transduction processes and exerts positive regulation effect. At present, the potential therapeutic application of hydrogen sulfide mainly focuses on the nervous and cardiovascular systems, such as the treatment of hypertension, the treatment of cardiac ischemic diseases, the treatment of atherosclerosis, and the combination with non-steroidal anti-inflammatory drugs to reduce the Metabolism, prevention of hypoxic damage, etc.
硫化氢供体在生理条件下可以水解自发放出H2S或在半胱氨酸(GSH)作用下释放H2S，GSH可以接受硫化物的S硫原子形成GSSH，然后通过3-巯基丙酮酸硫转移酶(3-MST)催化产生H2S。H2S的生物学效应及信号通路机制的研究揭示了其作为信号分子涉及在心血管系统、神经系统、循环系统等许多器官的细胞信号转导，对机体内多个生理过程都有影响。Under physiological conditions, hydrogen sulfide donors can hydrolyze and release H 2 S spontaneously or release H 2 S under the action of cysteine (GSH). GSH can accept the S sulfur atom of sulfide to form GSSH, and then pass 3-mercaptopyruvate Sulfur transferase (3-MST) catalyzes the generation of H 2 S. Studies on the biological effects and signaling pathway mechanism of H 2 S have revealed that as a signaling molecule, it is involved in cell signal transduction in many organs such as the cardiovascular system, nervous system, and circulatory system, and has an impact on multiple physiological processes in the body.
甘草次酸是甘草的主要药理活性物质。近年来，随着甘草次酸药理作用的研究不断深入，其药理作用日渐被认识，包括抗肿瘤、抗炎、抗病毒、治疗心血管疾病、免疫调节、抗氧化等多种药理作用。以天然产物为先导化合物，对其进行结构修饰引入相应活性的药效基团，进而进行相应领域的药理活性研究，已成为新药研发的研究热点。Glycyrrhetinic acid is the main pharmacological active substance of licorice. In recent years, as the research on the pharmacological effects of glycyrrhetinic acid continues to deepen, its pharmacological effects are increasingly recognized, including anti-tumor, anti-inflammatory, anti-viral, treatment of cardiovascular diseases, immune regulation, anti-oxidation and other pharmacological effects. Taking natural products as lead compounds, modifying their structure to introduce corresponding active pharmacophore, and then conducting research on pharmacological activity in corresponding fields has become a research hotspot in the development of new drugs.
目前尚未见有将甘草次酸与硫化氢供体试剂经烷烃链连接的衍生物及其合成方法和应用的相关报道。So far, there have been no related reports on the derivatives linking glycyrrhetinic acid and hydrogen sulfide donor reagents through alkane chains, their synthesis methods and applications.
发明内容Contents of the invention
本发明要解决的技术问题是提供一类结构新颖的甘草次酸-硫化氢供体试剂衍生物，以及它们的合成方法和应用。The technical problem to be solved by the present invention is to provide a class of novel glycyrrhetinic acid-hydrogen sulfide donor reagent derivatives, as well as their synthesis method and application.
本发明涉及具有下述通式(I)所示结构的甘草次酸-硫化氢供体试剂衍生物或其药学上可接受的盐：The present invention relates to a glycyrrhetinic acid-hydrogen sulfide donor reagent derivative or a pharmaceutically acceptable salt thereof having a structure represented by the following general formula (I):
其中，in,
n为2～8；n is 2 to 8;
R为 R is
本发明所述甘草次酸-硫化氢供体试剂衍生物的合成方法为：取甘草次酸、α,ω-二溴烷烃和碱在非质子极性溶剂中反应，得到化合物1；取化合物1、硫化氢供体试剂和碱在非质子极性溶剂中反应，得到目标物粗品；其中，反应在加热或不加热的条件下进行。The synthesis method of the glycyrrhetinic acid-hydrogen sulfide donor reagent derivative of the present invention is as follows: react glycyrrhetinic acid, α, ω-dibromoalkane and alkali in an aprotic polar solvent to obtain compound 1; 1. Reacting a hydrogen sulfide donor reagent and a base in an aprotic polar solvent to obtain a crude target product; wherein, the reaction is carried out under heating or non-heating conditions.
更为具体的合成方法，包括以下步骤：A more specific synthetic method comprises the following steps:
1)取甘草次酸、α,ω-二溴烷烃和碱在非质子极性溶剂中反应，所得反应物除去溶剂，残余物分散于乙酸乙酯、二氯甲烷或乙醚中，经洗涤，无水硫酸钠干燥，过滤后，收集滤液，滤液浓缩后得到化合物1；1) React glycyrrhetinic acid, α, ω-dibromoalkane and alkali in an aprotic polar solvent, remove the solvent from the obtained reactant, and disperse the residue in ethyl acetate, dichloromethane or ether, after washing, no dried over sodium sulfate, filtered, collected the filtrate, and concentrated the filtrate to obtain Compound 1;
2)取化合物1、硫化氢供体试剂和碱在非质子极性溶剂中反应，所得反应物除去溶剂，残余物分散于乙酸乙酯、二氯甲烷或乙醚中，经洗涤，无水硫酸钠干燥，过滤后，收集滤液，滤液浓缩后得到目标物粗品。2) Take compound 1, hydrogen sulfide donor reagent and base to react in an aprotic polar solvent, remove the solvent from the obtained reactant, and disperse the residue in ethyl acetate, dichloromethane or ether, after washing, anhydrous sodium sulfate After drying and filtering, the filtrate was collected, and the filtrate was concentrated to obtain the crude product of the target.
上述具体的合成方法的步骤1)和步骤2)中，所述的洗涤优选是依次用盐酸、水、饱和食盐水进行洗涤，或者是依次用盐酸、饱和食盐水进行洗涤。In step 1) and step 2) of the above specific synthesis method, the washing is preferably performed sequentially with hydrochloric acid, water, and saturated brine, or sequentially with hydrochloric acid, and saturated brine.
本发明所述合成方法中合成得到的化合物1的结构式如下所示：The structural formula of compound 1 synthesized in the synthetic method of the present invention is as follows:
其中，n为2～8。 Among them, n is 2-8.
上述方法中合成得到的化合物1为化合物1的粗品，为了提高化合物1的纯度同时减少后续反应中产生更多的副产物，优选是将所得化合物1的粗品经硅胶薄层色谱或硅胶柱层析纯化后再用于后续操作。在将其进行硅胶薄层色谱或上硅胶柱层析时，通常用由体积比为2～10：1的石油醚(PE)和乙酸乙酯(EA)组成的洗脱剂洗脱，收集洗脱液，洗脱液减压蒸除溶剂，得到纯化后的目标物。所述组成洗脱剂的石油醚和乙酸乙酯的体积比优选为2～5：1。The compound 1 synthesized in the above method is the crude product of compound 1. In order to improve the purity of compound 1 and reduce the production of more by-products in the subsequent reaction, it is preferred that the crude product of compound 1 be subjected to silica gel thin layer chromatography or silica gel column chromatography. Purified and then used in subsequent operations. When it is subjected to silica gel thin-layer chromatography or silica gel column chromatography, it is usually eluted with an eluent composed of petroleum ether (PE) and ethyl acetate (EA) at a volume ratio of 2 to 10:1, and the eluent is collected. Eluting, the eluent was evaporated under reduced pressure to remove the solvent, and the purified target product was obtained. The volume ratio of petroleum ether and ethyl acetate constituting the eluent is preferably 2-5:1.
由上述方法制得的是式(I)化合物的粗品，可采用现有常规的纯化方法对其进行纯化以提高式(I)化合物的纯度。通常采用硅胶薄层色谱或硅胶柱层析来进行纯化，在将制得的目标化合物粗品硅胶薄层色谱或上硅胶柱层析时，通常用由体积比为2～10：1的石油醚(PE)和乙酸乙酯(EA)组成的洗脱剂洗脱，收集洗脱液，洗脱液减压蒸除溶剂，得到纯化后的目标物。所述组成洗脱剂的石油醚和乙酸乙酯的体积比优选为2～5：1。The crude product of the compound of formula (I) obtained by the above method can be purified by existing conventional purification methods to improve the purity of the compound of formula (I). Silica gel thin-layer chromatography or silica gel column chromatography are usually used for purification. When the crude product of the target compound is subjected to silica gel thin-layer chromatography or upper silica gel column chromatography, petroleum ether ( PE) and ethyl acetate (EA), the eluent was collected, and the eluent was evaporated under reduced pressure to remove the solvent to obtain the purified target substance. The volume ratio of petroleum ether and ethyl acetate constituting the eluent is preferably 2-5:1.
本发明所述的合成方法中，所述的α,ω-二溴烷烃可以是1,2-二溴乙烷、1,3-二溴丙烷、1,4-二溴丁烷、1,5-二溴戊烷、1,6-二溴己烷、1,7-二溴庚烷或1,8-二溴辛烷。In the synthesis method described in the present invention, the α, ω-dibromoalkane can be 1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromobutane, 1,5 - Dibromopentane, 1,6-dibromohexane, 1,7-dibromoheptane or 1,8-dibromooctane.
本发明所述的合成方法中，所述的碱可以是碳酸钾、三乙胺、碳酸钠、碳酸氢钠、碳酸氢钾或碳酸铯。当碱的选择为碳酸铯时，可以获得更高的产率；从成本及产率综合考虑，优选碱为碳酸钾。In the synthetic method of the present invention, the base can be potassium carbonate, triethylamine, sodium carbonate, sodium bicarbonate, potassium bicarbonate or cesium carbonate. When the selection of the base is cesium carbonate, a higher yield can be obtained; from the comprehensive consideration of cost and yield, the preferred base is potassium carbonate.
本发明所述的合成方法中，所所述的非质子极性溶剂可以是N,N-二甲基甲酰胺(DMF)、甲苯和吡啶中的一种或两种以上的组合，当非质子极性溶剂的选择是上述两种以上的组合时，它们之间的配比可以为任意配比。所述非质子极性溶剂的用量通常为能够溶解参加反应的原料即可。In the synthetic method described in the present invention, described aprotic polar solvent can be one or the combination of two or more in N,N-dimethylformamide (DMF), toluene and pyridine, when aprotic When the choice of the polar solvent is a combination of the above two or more, the ratio between them can be any ratio. The amount of the aprotic polar solvent is usually enough to dissolve the raw materials participating in the reaction.
本发明所述的合成方法中，所述的硫化氢供体试剂具体可以是5-对羟基苯基-1,2-二硫杂环戊烯-3-硫酮(ADT-OH)、(R)-硫辛酸(R-lipoic acid)或4-羟基硫代苯甲酰胺(TBZ)，它们的结构式分别如下所示：In the synthetic method of the present invention, the hydrogen sulfide donor reagent can specifically be 5-p-hydroxyphenyl-1,2-dithiole-3-thione (ADT-OH), (R )-lipoic acid (R-lipoic acid) or 4-hydroxythiobenzamide (TBZ), their structural formulas are as follows respectively:
本发明所述的合成方法中，所述甘草次酸、α,ω-二溴烷烃和碱的反应优选是在低于或等于40℃的条件下进行，申请人在实验中发现，当反应在20～40℃条件下进行时，可以在较短的时间内获得较高的产率，同时副反应较少；所述化合物1、硫化氢供体试剂和碱的反应在低于或等于65℃的条件下进行，更优选是在35～65℃条件下进行，这样可以在较短的时间内获得较高的产率，并尽量减少副产物的生成。在上述限定温度条件下，反应是否完全可以通过薄层层析跟踪检测。In the synthesis method of the present invention, the reaction of glycyrrhetinic acid, α, ω-dibromoalkane and alkali is preferably carried out at a temperature lower than or equal to 40°C. The applicant found in experiments that when the reaction is When carried out at 20-40°C, a higher yield can be obtained in a shorter period of time with fewer side reactions; the reaction of the compound 1, the hydrogen sulfide donor reagent and the base is lower than or equal to 65°C It is carried out under the condition of 35-65 ℃ more preferably, so that a higher yield can be obtained in a shorter time and the generation of by-products can be minimized. Under the above-mentioned limited temperature conditions, whether the reaction is complete can be tracked and detected by thin layer chromatography.
本发明所述的合成方法中，所述甘草次酸、α,ω-二溴烷烃和碱的物质的量之比为：1：1～5：0.5～3；所述化合物1、硫化氢供体试剂和碱的物质的量之比为：1：1～3：1～5。In the synthesis method of the present invention, the ratio of the amount of glycyrrhetinic acid, α, ω-dibromoalkane and alkali is: 1:1～5:0.5～3; the compound 1, hydrogen sulfide supply The ratio of the amount of bulk reagent and alkali is: 1:1～3:1～5.
申请人发现，在化合物1、硫化氢供体试剂和碱的反应中，加入催化剂碘化钾(KI)可以进一步提高目标物的产率。所述碘化钾的加入量为化合物1物质的量的0.1～1倍。The applicant found that in the reaction of compound 1, hydrogen sulfide donor reagent and base, adding catalyst potassium iodide (KI) can further increase the yield of the target product. The amount of potassium iodide added is 0.1 to 1 times the amount of compound 1 substance.
与现有技术相比，本发明提供了一系列结构新颖的甘草次酸-硫化氢供体试剂衍生物及其合成方法，同时，申请人还考察了这些衍生物对肝癌肿瘤细胞株及慢性骨髓性白血病细胞的抑制活性，结果表明，其中大部分化合物对慢性骨髓性白血病细胞K562具有一定的抑制活性，有望用于相应的抗肿瘤药物及治疗慢性骨髓性白血病的药物的制备。Compared with the prior art, the present invention provides a series of novel glycyrrhetinic acid-hydrogen sulfide donor reagent derivatives and their synthesis methods. Meanwhile, the applicant has also investigated the effect of these derivatives on liver cancer tumor cell lines and chronic bone marrow The results show that most of the compounds have certain inhibitory activity on chronic myelogenous leukemia cell K562, and are expected to be used in the preparation of corresponding antineoplastic drugs and drugs for treating chronic myelogenous leukemia.
具体实施方式Detailed ways
下面结合具体实施例对本发明作进一步的详述,以更好地理解本发明的内容,但本发明并不限于以下实施例。The present invention will be described in further detail below in conjunction with specific examples to better understand the content of the present invention, but the present invention is not limited to the following examples.
本发明所述的具有下述通式(I)所示结构的甘草次酸-硫化氢供体试剂衍生物按下述合成路线进行合成：Glycyrrhetinic acid-hydrogen sulfide donor reagent derivatives having the structure shown in the following general formula (I) according to the present invention are synthesized according to the following synthetic route:
其中：in:
α,ω-二溴烷烃可以是1,2-二溴乙烷、1,3-二溴丙烷、1,4-二溴丁烷、1,5-二溴戊烷、1,6-二溴己烷、1,7-二溴庚烷或1,8-二溴辛烷；α,ω-Dibromoalkane can be 1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromobutane, 1,5-dibromopentane, 1,6-dibromo Hexane, 1,7-dibromoheptane or 1,8-dibromooctane;
非质子极性溶剂可以是N,N-二甲基甲酰胺、甲苯或吡啶；The aprotic polar solvent can be N,N-dimethylformamide, toluene or pyridine;
碱可以是碳酸钾、三乙胺、碳酸钠、碳酸氢钠、碳酸氢钾或碳酸铯；The base can be potassium carbonate, triethylamine, sodium carbonate, sodium bicarbonate, potassium bicarbonate or cesium carbonate;
硫化氢供体试剂具体可以是5-对羟基苯基-1,2-二硫杂环戊烯-3-硫酮(ADT-OH)、(R)-硫辛酸(R-lipoic acid)或4-羟基硫代苯甲酰胺(TBZ)，它们的结构式分别如下所示：The hydrogen sulfide donor reagent can specifically be 5-p-hydroxyphenyl-1,2-dithiol-3-thione (ADT-OH), (R)-lipoic acid (R-lipoic acid) or 4 -Hydroxythiobenzamide (TBZ), their structural formulas are as follows respectively:
化合物1和化合物2中的n为2～8；n in compound 1 and compound 2 is 2-8;
化合物2中的R为 R in compound 2 is
实施例1：化合物1a的合成Embodiment 1: the synthesis of compound 1a
将甘草次酸(500mg,1.06mmol)溶于无水DMF(5mL)，加入1,6-二溴乙烷(2.43mL,5.3mmol)、K2CO3(146.28mg,1.06mmol)，30℃反应24h。减压蒸除溶剂，残余物分散乙酸乙酯(50mL)中，依次用HCl(1N)、水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析分离(VPE:VEA＝2:1)，得化合物1a(457mg,75％,白色固体)。Dissolve glycyrrhetinic acid (500mg, 1.06mmol) in anhydrous DMF (5mL), add 1,6-dibromoethane (2.43mL, 5.3mmol), K 2 CO 3 (146.28mg, 1.06mmol), 30°C Reaction 24h. The solvent was evaporated under reduced pressure, and the residue was dispersed in ethyl acetate (50 mL), washed successively with HCl (1N), water, and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V PE : V EA =2:1), to obtain compound 1a (457 mg, 75%, white solid).
Yield:457mg,75％,white solid；Rf＝0.461(Petroluem ether:EtOAc＝2:1).M.p 190-192℃.1H NMR(500MHz,CDCl3)δ(ppm):5.69(s,1H,12-H),4.41(dd,J＝28.0,5.9Hz,2H,OCH2),3.53(t,J＝5.7Hz,2H,OCH2),3.21(dd,J＝11.0,5.2Hz,1H,3-H),2.83-2.71(m,1H,18-H),2.32(s,1H),2.21-0.63(m,20H),1.35,1.17,1.12,1.11,0.99,0.80and0.79(7s,each 3H,7×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.3,176.2,169.2,128.8,78.9,63.9,61.9,55.1,48.3,45.5,44.3,43.3,41.0,39.2,37.8,37.2,32.9,32.0,31.2,29.2,28.6,28.2,27.4,26.6,23.5,18.8,17.6,16.5,15.7.HRMS(ESI)m/z:[M+H]+calcdfor C32H50BrO4,577.2893；found 577.2873.Yield: 457mg, 75%, white solid; R f ＝0.461 (Petroluem ether:EtOAc＝2:1).Mp 190-192℃. 1 H NMR (500MHz, CDCl 3 )δ(ppm): 5.69(s, 1H ,12-H),4.41(dd,J=28.0,5.9Hz,2H,OCH 2 ),3.53(t,J=5.7Hz,2H,OCH 2 ),3.21(dd,J=11.0,5.2Hz,1H ,3-H),2.83-2.71(m,1H,18-H),2.32(s,1H),2.21-0.63(m,20H),1.35,1.17,1.12,1.11,0.99,0.80and0.79( 7s,each 3H,7×CH 3 ). 13 C NMR(125MHz,CDCl 3 )δ(ppm):200.3,176.2,169.2,128.8,78.9,63.9,61.9,55.1,48.3,45.5,44.3,43.3,41.0 ,39.2,37.8,37.2,32.9,32.0,31.2,29.2,28.6,28.2,27.4,26.6,23.5,18.8,17.6,16.5,15.7.HRMS(ESI)m/z:[M+H] + calcdfor C 32 H 50 BrO 4 , 577.2893; found 577.2873.
实施例2：化合物1b的合成Embodiment 2: the synthesis of compound 1b
将甘草次酸(500mg,1.06mmol)溶于无水DMF(5mL)，加入1,8-二溴丁烷(2.94mL,5.3mmol)、K2CO3(146.28mg,1.06mmol)，30℃反应24h。减压蒸除溶剂，残余物分散乙酸乙酯(50mL)中，依次用HCl(1N)、水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析分离(VPE:VEA＝2:1)，得化合物1b(532mg,83％,白色固体)。Dissolve glycyrrhetinic acid (500mg, 1.06mmol) in anhydrous DMF (5mL), add 1,8-dibromobutane (2.94mL, 5.3mmol), K 2 CO 3 (146.28mg, 1.06mmol), 30°C Reaction 24h. The solvent was evaporated under reduced pressure, and the residue was dispersed in ethyl acetate (50 mL), washed successively with HCl (1N), water, and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V PE : V EA =2:1), to obtain compound 1b (532 mg, 83%, white solid).
Yield:532mg,83％,white solid；Rf＝0.515(Petroluem ether:EtOAc＝2:1).M.p 82-84℃.1H NMR(500MHz,CDCl3)δ(ppm):5.61(s,1H,12-H),4.12(t,J＝6.3Hz,2H,OCH2),3.43(t,J＝6.5Hz,2H,OCH2),3.21(dd,J＝11.1,5.1Hz,1H,3-H),2.77(d,J＝13.5Hz,1H,18-H),2.32(s,1H),2.13-0.61(m,24H),1.35,1.14,1.11,1.10and 0.98(5s,each 3H,5×CH3),0.79(s,6H,2×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.3,176.5 169.3,128.6,78.8,63.5,61.9,55.0,48.5,45.5,44.1,43.3,41.1,39.2,37.8,37.2,33.1,32.8,31.9,31.2,29.4,28.6,28.2,27.4,26.5,23.5,18.8,17.6,16.5,15.7.HRMS(ESI)m/z:[M+H]+calcd for C34H54BrO4,605.3206；found 605.3188.Yield: 532mg, 83%, white solid; R f ＝0.515 (Petroluem ether:EtOAc＝2:1).Mp 82-84℃. 1 H NMR (500MHz, CDCl 3 )δ(ppm): 5.61(s, 1H ,12-H),4.12(t,J=6.3Hz,2H,OCH 2 ),3.43(t,J=6.5Hz,2H,OCH 2 ),3.21(dd,J=11.1,5.1Hz,1H,3 -H),2.77(d,J＝13.5Hz,1H,18-H),2.32(s,1H),2.13-0.61(m,24H),1.35,1.14,1.11,1.10and 0.98(5s,each 3H ,5×CH 3 ),0.79(s,6H,2×CH 3 ). 13 C NMR(125MHz,CDCl 3 )δ(ppm):200.3,176.5 169.3,128.6,78.8,63.5,61.9,55.0,48.5, HRMS(ESI)m/z: [M+H] + calcd for C 34 H 54 BrO 4 , 605.3206; found 605.3188.
实施例3：化合物1c的合成Embodiment 3: the synthesis of compound 1c
将甘草次酸(1.0g,2.12mmol)溶于无水DMF(5mL)，加入1,6-二溴己烷(1.62mL,10.62mmol)、K2CO3(293.0mg,2.12mmol)，30℃反应24h。减压蒸除溶剂，残余物分散乙酸乙酯(50ml)中，依次用HCl(1N)、水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析分离(VPE:VEA＝5:2)，得化合物1c(929mg,69％,白色固体)。Dissolve glycyrrhetinic acid (1.0g, 2.12mmol) in anhydrous DMF (5mL), add 1,6-dibromohexane (1.62mL, 10.62mmol), K 2 CO 3 (293.0mg, 2.12mmol), 30 ℃ reaction 24h. The solvent was evaporated under reduced pressure, the residue was dispersed in ethyl acetate (50ml), washed successively with HCl (1N), water, and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V PE : V EA =5:2), to obtain compound 1c (929 mg, 69%, white solid).
Yield:929mg,69％,white solid；Rf＝0.452(Petroluem ether:EtOAc＝5:2).M.p 102-104℃.1H NMR(500MHz,CDCl3)δ(ppm):5.61(s,1H,12-H),4.08(m,2H,OCH2),3.39(m,2H,CH2-Br),3.20(dd,J＝11.1,5.2Hz,1H,3-H),2.76(d,J＝13.5Hz,1H,18-H),2.32(s,1H,10-H),2.09-0.69(m,35H),1.35,1.13,1.11,1.10and 0.98(5s,each 3H,5×CH3),0.79(s,6H,2×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.3,176.6,169.4,128.6,61.9,78.8,64.4,55.0,48.5,45.5,44.1,43.3,41.2,39.2,37.9,37.2,33.9,32.9,32.7 31.9,31.2,28.7,28.5,28.2,27.8,27.4,26.6,26.5,25.4,23.5,18.8,17.6,16.5,15.7.HRMS(ESI)m/z:[M+H]+calcd for C36H58BrO4,633.3519；found633.3525.Yield: 929mg, 69%, white solid; R f ＝0.452 (Petroluem ether:EtOAc＝5:2).Mp 102-104℃. 1 H NMR (500MHz, CDCl 3 )δ(ppm): 5.61(s, 1H ,12-H), 4.08(m,2H,OCH 2 ),3.39(m,2H,CH 2 -Br),3.20(dd,J=11.1,5.2Hz,1H,3-H),2.76(d, J=13.5Hz, 1H, 18-H), 2.32(s, 1H, 10-H), 2.09-0.69(m, 35H), 1.35, 1.13, 1.11, 1.10 and 0.98(5s, each 3H, 5×CH 3 ),0.79(s,6H,2×CH 3 ). 13 C NMR(125MHz,CDCl 3 )δ(ppm):200.3,176.6,169.4,128.6,61.9,78.8,64.4,55.0,48.5,45.5,44.1 ,43.3,41.2,39.2,37.9,37.2,33.9,32.9,32.7 31.9,31.2,28.7,28.5,28.2,27.8,27.4,26.6,26.5,25.4,23.5,18.8,17.6,16.5,15.7 m/z: [M+H] + calcd for C 36 H 58 BrO 4 , 633.3519; found 633.3525.
实施例4：化合物1d的合成Embodiment 4: the synthesis of compound 1d
将甘草次酸(1.0g,2.12mmol)溶于无水DMF(5mL)，加入1,8-二溴辛烷(1.62mL,10.62mmol)、K2CO3(293.0mg,2.12mmol)，30℃反应24h。减压蒸除溶剂，残余物分散乙酸乙酯(50mL)中，依次用HCl(1N)、水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析分离(VPE:VEA＝5:2)，得化合物1d(984mg,62％,白色固体)。Dissolve glycyrrhetinic acid (1.0g, 2.12mmol) in anhydrous DMF (5mL), add 1,8-dibromooctane (1.62mL, 10.62mmol), K 2 CO 3 (293.0mg, 2.12mmol), 30 ℃ reaction 24h. The solvent was evaporated under reduced pressure, and the residue was dispersed in ethyl acetate (50 mL), washed successively with HCl (1N), water, and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V PE : V EA =5:2), to obtain compound 1d (984 mg, 62%, white solid).
Yield:984mg,62％,white solid；Rf＝0.500(Petroluem ether:EtOAc＝5:2).M.p 67-69℃.1H NMR(500MHz,CDCl3)δ(ppm):5.62(s,1H,12-H),4.07(m,2H,OCH2),3.39(m,2H,CH2-Br),3.21(dd,J＝11.1,5.2Hz,1H,3-H),2.77(d,J＝13.6Hz,1H,18-H),2.32(s,1H,10-H),2.10-0.69(m,35H),1.35,1.13,1.12,1.11and 0.99(5s,each 3H,5×CH3),0.79(s,6H,2×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.3,176.6,169.4,128.6,78.9,64.6,61.9,55.1,48.5,45.5,44.1,43.3,41.2,39.2,37.9,34.1,37.2,32.9,31.9,31.3,29.1,28.7,28.8,28.7,28.6,28.3,28.2,27.4,26.6,26.5,26.0,23.5,18.8,17.6,16.5,15.7.HRMS(ESI)m/z:[M+H]+calcd for C38H62BrO4,661.3831；found 661.3836.Yield: 984mg, 62%, white solid; R f ＝0.500(Petroluem ether:EtOAc＝5:2).Mp 67-69℃. 1 H NMR (500MHz, CDCl 3 )δ(ppm): 5.62(s, 1H ,12-H), 4.07(m,2H,OCH 2 ),3.39(m,2H,CH 2 -Br),3.21(dd,J=11.1,5.2Hz,1H,3-H),2.77(d, J=13.6Hz, 1H, 18-H), 2.32(s, 1H, 10-H), 2.10-0.69(m, 35H), 1.35, 1.13, 1.12, 1.11 and 0.99(5s, each 3H, 5×CH 3 ),0.79(s,6H,2×CH 3 ). 13 C NMR(125MHz,CDCl 3 )δ(ppm):200.3,176.6,169.4,128.6,78.9,64.6,61.9,55.1,48.5,45.5,44.1 ,43.3,41.2,39.2,37.9,34.1,37.2,32.9,31.9,31.3,29.1,28.7,28.8,28.7,28.6,28.3,28.2,27.4,26.6,26.5,26.0,23.5,18.8,17.6,16.5,15.7 .HRMS (ESI) m/z: [M+H] + calcd for C 38 H 62 BrO 4 , 661.3831; found 661.3836.
实施例5：化合物2a的合成Embodiment 5: the synthesis of compound 2a
将化合物1a(250mg,0.43mmol)溶于DMF(5mL)，加入(R)-lipoicacid(88.58mg,0.43mmol)、K2CO3(178.02mg,1.29mmol)，50℃反应24h。残余物分散在乙酸乙酯(50mL)，依次用HCl(1N)、水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析分离(VPE:VEA＝2:1)，得化合物2a(231mg,76％,淡黄色固体)。Compound 1a (250mg, 0.43mmol) was dissolved in DMF (5mL), (R)-lipoicacid (88.58mg, 0.43mmol) and K 2 CO 3 (178.02mg, 1.29mmol) were added, and reacted at 50°C for 24h. The residue was dispersed in ethyl acetate (50 mL), washed successively with HCl (1N), water, and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V PE : V EA =2 :1), to obtain compound 2a (231mg, 76%, pale yellow solid).
Yield:231mg,76％,yellow solid；Rf＝0.490(Petroluem ether:EtOAc＝2:1).M.p 64-66℃.1H NMR(500MHz,CDCl3)δ(ppm):5.62(s,1H,12-H),4.41-4.18(m,4H,2×OCH2),3.52(dd,J＝8.2,6.4Hz,1H,3-H),3.25-2.98(m,3H),2.75(d,J＝13.5Hz,1H,18-H),2.44(s,1H),2.33(dd,J＝14.7,7.2Hz,3H),2.14-0.60(m,26H),1.34,1.13,1.10,1.09,0.97,0.78and 0.77(7s,each 3H,7×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.1,176.2,173.3,169.2,128.5,78.8,62.3,61.9,56.4,55.0,48.4,45.5,44.1,43.3,41.1,40.3,39.2,38.6,37.8,37.2,34.6,34.0,32.8,31.9,31.2,28.8,28.7,28.3,28.2,27.3,26.5,24.6,23.5,18.8,17.6,16.4,15.7,14.3.HRMS(ESI)m/z:[M+H]+calcdfor C40H62ClO6S2,737.3676；found 737.3696.Yield: 231 mg, 76%, yellow solid; R f =0.490 (Petroluem ether:EtOAc=2:1).Mp 64-66°C. 1 H NMR (500MHz, CDCl 3 )δ(ppm): 5.62(s, 1H ,12-H),4.41-4.18(m,4H,2×OCH 2 ),3.52(dd,J＝8.2,6.4Hz,1H,3-H),3.25-2.98(m,3H),2.75(d ,J=13.5Hz,1H,18-H),2.44(s,1H),2.33(dd,J=14.7,7.2Hz,3H),2.14-0.60(m,26H),1.34,1.13,1.10,1.09 ,0.97,0.78and 0.77(7s,each 3H,7×CH 3 ). 13 C NMR(125MHz,CDCl 3 )δ(ppm):200.1,176.2,173.3,169.2,128.5,78.8,62.3,61.9,56.4, 55.0, 48.4, 45.5, 44.1, 43.3, 41.1, 40.3, 39.2, 38.6, 37.8, 37.2, 34.6, 34.0, 32.8, 31.9, 31.2, 28.8, 28.7, 28.3, 28.2, 27.3, 26.5, 24.6, 23.5, 18.8, 17.6, 16.4, 15.7, 14.3. HRMS (ESI) m/z: [M+H] + calcdfor C 40 H 62 ClO 6 S 2 , 737.3676; found 737.3696.
实施例6：化合物2b的合成Embodiment 6: the synthesis of compound 2b
将化合物1b(250mg,0.41mmol)溶于DMF(5mL)F，加入(R)-lipoicacid(85.12mg,0.41mmol)、K2CO3(169.74mg,1.23mmol)，50℃反应24h。残余物分散在乙酸乙酯(50mL)，依次用HCl(1N)、水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析分离(VPE:VEA＝2:1)，得化合物2b(190mg,63％,淡黄色固体)。Dissolve compound 1b (250 mg, 0.41 mmol) in DMF (5 mL) F, add (R)-lipoicacid (85.12 mg, 0.41 mmol), K 2 CO 3 (169.74 mg, 1.23 mmol), and react at 50°C for 24 h. The residue was dispersed in ethyl acetate (50 mL), washed successively with HCl (1N), water, and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V PE : V EA =2 : 1), to obtain compound 2b (190mg, 63%, pale yellow solid).
Yield:190mg,63％,yellow solid；Rf＝0.431(Petroluem ether:EtOAc＝2:1).M.p 60-62℃.1H NMR(500MHz,CDCl3)δ(ppm):5.60(s,1H,12-H),4.09(m,4H,2×OCH2),3.54(dd,J＝8.2,6.4Hz,1H,3-H),3.21-3.02(m,3H),2.75(dd,J＝13.3,3.3Hz,1H,18-H),2.45(s,1H),2.30(dd,J＝9.8,4.7Hz,3H),2.15-0.61(m,30H),1.34,1.13,1.10,1.09and0.98(5s,each 3H,5×CH3),0.78(s,6H,2×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.2,176.5,173.6,169.3,128.6,78.8,63.9,61.9,56.4,55.0,48.5,45.5,44.1,43.3,41.1,40.3,39.2,38.6,37.8,37.2,34.7,34.1,32.8,31.9,31.2,28.8,28.7,28.5,28.2,27.4,26.6,26.5,25.6,25.5,24.7,23.5,18.8,17.6,16.5,15.7.HRMS(ESI)m/z:[M+H]+calcdfor C42H66ClO6S2,765.3989；found 765.4008.Yield: 190mg, 63%, yellow solid; R f ＝0.431 (Petroluem ether:EtOAc＝2:1).Mp 60-62℃. 1 H NMR (500MHz, CDCl 3 )δ(ppm): 5.60(s, 1H ,12-H), 4.09(m,4H,2×OCH 2 ),3.54(dd,J＝8.2,6.4Hz,1H,3-H),3.21-3.02(m,3H),2.75(dd,J =13.3,3.3Hz,1H,18-H),2.45(s,1H),2.30(dd,J=9.8,4.7Hz,3H),2.15-0.61(m,30H),1.34,1.13,1.10,1.09 and0.98(5s,each 3H,5×CH 3 ),0.78(s,6H,2×CH 3 ). 13 C NMR(125MHz,CDCl 3 )δ(ppm):200.2,176.5,173.6,169.3,128.6 ,78.8,63.9,61.9,56.4,55.0,48.5,45.5,44.1,43.3,41.1,40.3,39.2,38.6,37.8,37.2,34.7,34.1,32.8,31.9,31.2,28.8,28.7,28.5,28.2,27.4 ,26.6,26.5,25.6,25.5,24.7,23.5,18.8,17.6,16.5,15.7.HRMS(ESI)m/z:[M+H] + calcdfor C 42 H 66 ClO 6 S 2 ,765.3989;
实施例7：化合物2c的合成Embodiment 7: the synthesis of compound 2c
将化合物1c(500mg,0.79mmol)溶于DMF(5mL)，加入(R)-lipoicacid(163.0mg,0.79mmol)、K2CO3(327.58mg,2.37mmol)，50℃反应24h。残余物分散在乙酸乙酯(50mL)，依次用HCl(1N)、水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析分离(VPE:VEA＝3:1)，得化合物2c(402mg,67％,淡黄色固体)。Compound 1c (500mg, 0.79mmol) was dissolved in DMF (5mL), (R)-lipoicacid (163.0mg, 0.79mmol) and K 2 CO 3 (327.58mg, 2.37mmol) were added, and reacted at 50°C for 24h. The residue was dispersed in ethyl acetate (50 mL), washed successively with HCl (1N), water, and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V PE : V EA =3 :1), to obtain compound 2c (402mg, 67%, pale yellow solid).
Yield:402mg,67％,yellow solid；Rf＝0.339(Petroluem ether:EtOAc＝3:1).M.p 51-53℃.1H NMR(400MHz,CDCl3)δ(ppm):5.60(s,1H,12-H),4.05(m,4H,2×OCH2),3.54(dd,J＝8.0,6.5Hz,1H,3-H),3.25-3.03(m,3H),2.75(dd,J＝10.1,3.4Hz,1H,18-H),2.42(m,1H),2.29(m,2H),2.12-0.58(m,36H),1.35(s,3H,CH3),1.12–1.04(m,9H,3×CH3),0.97(s,3H,CH3),0.77(s,6H,2×CH3).13C NMR(100MHz,CDCl3)δ(ppm):200.2,176.5,173.6,169.3,128.6,78.8,64.4,61.9,56.4,55.0,48.5,45.5,44.1,43.3,41.2,40.3,39.2,38.5,37.8,37.2,34.7,34.2,32.8,31.9,31.2,28.6,28.2,27.4,26.5,25.8,25.6,24.8,23.5,18.8,17.6,16.4,15.7.HRMS(ESI)m/z:[M+H]+calcd for C44H71O6S2,759.4692；found759.4696.Yield: 402 mg, 67%, yellow solid; R f =0.339 (Petroluem ether:EtOAc=3:1).Mp 51-53°C. 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 5.60 (s, 1H ,12-H),4.05(m,4H,2×OCH 2 ),3.54(dd,J＝8.0,6.5Hz,1H,3-H),3.25-3.03(m,3H),2.75(dd,J ＝10.1,3.4Hz,1H,18-H),2.42(m,1H),2.29(m,2H),2.12-0.58(m,36H),1.35(s,3H,CH 3 ),1.12–1.04( m,9H,3×CH 3 ),0.97(s,3H,CH 3 ),0.77(s,6H,2×CH 3 ). 13 C NMR(100MHz,CDCl 3 )δ(ppm):200.2,176.5, 173.6, 169.3, 128.6, 78.8, 64.4, 61.9, 56.4, 55.0, 48.5, 45.5, 44.1, 43.3, 41.2, 40.3, 39.2, 38.5, 37.8, 37.2, 34.7, 34.2, 32.8, 31.9, 31.2, 22.6, 28. 27.4, 26.5, 25.8, 25.6, 24.8, 23.5, 18.8, 17.6, 16.4, 15.7. HRMS (ESI) m/z: [M+H] + calcd for C 44 H 71 O 6 S 2 , 759.4692; found759.4696 .
实施例8：化合物2d的合成Embodiment 8: the synthesis of compound 2d
将化合物1d(500mg,0.76mmol)溶于DMF(5mL)，加入(R)-lipoicacid(156.81mg,0.76mmol)、K2CO3(315.12mg,2.28mmol)，50℃反应24h。残余物分散在乙酸乙酯(50mL)，依次用HCl(1N)、水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析分离(VPE:VEA＝3:1)，得化合物2d(475mg,80％,淡黄色固体)。Compound 1d (500mg, 0.76mmol) was dissolved in DMF (5mL), (R)-lipoicacid (156.81mg, 0.76mmol) and K 2 CO 3 (315.12mg, 2.28mmol) were added and reacted at 50°C for 24h. The residue was dispersed in ethyl acetate (50 mL), washed successively with HCl (1N), water, and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V PE : V EA =3 :1), to obtain compound 2d (475mg, 80%, pale yellow solid).
Yield:475mg,80％,yellow solid；Rf＝0.578(Petroluem ether:EtOAc＝3:1).M.p 52-54℃.1H NMR(400MHz,CDCl3)δ(ppm):5.60(s,1H,H-12),4.13-3.97(s,4H,2×OCH2),3.53(m,1H,3-H),3.27(m,3H),2.74(d,J＝13.5Hz,1H,18-H),2.42(dd,J＝12.5,6.2Hz,1H),2.28(dd,J＝13.7,6.3Hz,3H),2.10-0.60(m,40H),1.12-1.05(m,9H,2×CH3),0.96(s,6H,2×CH3),0.77(s,6H,2×CH3).13C NMR(100MHz,CDCl3)δ(ppm):200.2,176.5,173.6,169.3,128.5,78.7,64.5,61.9,56.4,55.0,48.4,45.4,44.0,43.3,41.1,40.2,39.2,38.5,37.8,37.1,34.6,34.1,32.8,31.9,31.2,29.1,28.8,28.7,28.6,28.5,28.2,27.4,26.5,25.9,24.8,23.5,18.7,17.5,16.4,15.7.HRMS(ESI)m/z:[M+H]+calcd forC46H75O6S2,787.5005；found 787.5019.Yield: 475 mg, 80%, yellow solid; R f =0.578 (Petroluem ether:EtOAc=3:1).Mp 52-54°C. 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 5.60 (s, 1H ,H-12),4.13-3.97(s,4H,2×OCH 2 ),3.53(m,1H,3-H),3.27(m,3H),2.74(d,J＝13.5Hz,1H,18 -H), 2.42(dd, J＝12.5, 6.2Hz, 1H), 2.28(dd, J＝13.7, 6.3Hz, 3H), 2.10-0.60(m, 40H), 1.12-1.05(m, 9H, 2 ×CH 3 ),0.96(s,6H,2×CH 3 ),0.77(s,6H,2×CH 3 ). 13 C NMR(100MHz,CDCl 3 )δ(ppm):200.2,176.5,173.6,169.3 . found _ _ _ _ 787.5019.
实施例9：化合物2e的合成Embodiment 9: the synthesis of compound 2e
将化合物1c(500mg,0.79mmol)溶于DMF(5mL)，加入ADT-OH(178.57mg,0.79mmol)、K2CO3(327.58mg,2.37mmol)、KI(13.28mg,0.08mmol)，65℃反应24h。残余物分散在乙酸乙酯(50mL)，依次用HCl(1N)、水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析分离(VPE:VEA＝3:1)，得化合物2e(126mg,21％,橙色固体)。Compound 1c (500mg, 0.79mmol) was dissolved in DMF (5mL), ADT-OH (178.57mg, 0.79mmol), K 2 CO 3 (327.58mg, 2.37mmol), KI (13.28mg, 0.08mmol), 65 ℃ reaction 24h. The residue was dispersed in ethyl acetate (50 mL), washed successively with HCl (1N), water, and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V PE : V EA =3 :1), to obtain compound 2e (126mg, 21%, orange solid).
Yield:126mg,21％,orange solid；Rf＝0.352(Petroluem ether:EtOAc＝3:1).M.p 92-94℃.1H NMR(400MHz,CDCl3)δ(ppm):7.60(d,J＝8.8Hz,2H,Ar-H),7.39(s,1H,Ar-H),6.96(d,J＝8.8Hz,2H,Ar-H),5.63(s,1H,12-H),4.22-3.97(m,4H,2×OCH2),3.23(dd,J＝10.9,5.3Hz,1H,3-H),2.79(d,J＝13.5Hz,1H,18-H),2.34(s,1H,9-H),2.13-0.69(m,29H),1.19-1.09(m,9H,3×CH3),1.01(s,6H,2×CH3),0.81(s,6H,2×CH3).13CNMR(100MHz,CDCl3)δ(ppm):215.1,200.3,176.6,173.3,169.5,162.6,134.6,128.7,128.6,124.0,115.6,78.8,68.3,64.4,61.9,55.0,48.6,45.5,44.1,43.3,41.2,39.2,37.8,37.2,32.9,31.9,31.2,29.0,28.8,28.7,28.5,28.2,27.4,26.54,26.51,25.9,25.7,23.5,18.8,17.6,16.5,15.7.HRMS(APCl)m/z:[M+H]+calcd for C45H63O5S3,779.3838；found 779.3820.Yield: 126mg, 21%, orange solid; Rf = 0.352 (Petroluem ether:EtOAc = 3:1). Mp 92-94°C. 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.60 (d, J =8.8Hz,2H,Ar-H),7.39(s,1H,Ar-H),6.96(d,J=8.8Hz,2H,Ar-H),5.63(s,1H,12-H),4.22 -3.97(m,4H,2×OCH 2 ),3.23(dd,J＝10.9,5.3Hz,1H,3-H),2.79(d,J＝13.5Hz,1H,18-H),2.34(s ,1H,9-H),2.13-0.69(m,29H),1.19-1.09(m,9H,3×CH 3 ),1.01(s,6H,2×CH 3 ),0.81(s,6H,2 ×CH 3 ). 13 CNMR(100MHz,CDCl 3 )δ(ppm):215.1,200.3,176.6,173.3,169.5,162.6,134.6,128.7,128.6,124.0,115.6,78.8,68.3,64.4,61.9,55.0, 48.6, 45.5, 44.1, 43.3, 41.2, 39.2, 37.8, 37.2, 32.9, 31.9, 31.2, 29.0, 28.8, 28.7, 28.5, 28.2, 27.4, 26.54, 26.51, 25.9, 25.7, 23.5, 18.8, 17, 6, 16.5 15.7. HRMS (APCl) m/z: [M+H] + calcd for C 45 H 63 O 5 S 3 , 779.3838; found 779.3820.
实施例10：化合物2f的合成Embodiment 10: the synthesis of compound 2f
将化合物1d(500mg,0.76mmol)溶于DMF(5mL)，加入ADT-OH(169.74mg,0.76mmol)、K2CO3(315.12mg,2.28mmol)、KI(13.28mg,0.08mmol)，65℃反应24h。残余物分散在乙酸乙酯(50mL)，依次用HCl(1N)、水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析分离(VPE:VEA＝3:1)，得化合物2f(118mg,19％,橙色固体)。Compound 1d (500mg, 0.76mmol) was dissolved in DMF (5mL), ADT-OH (169.74mg, 0.76mmol), K 2 CO 3 (315.12mg, 2.28mmol), KI (13.28mg, 0.08mmol), 65 ℃ reaction 24h. The residue was dispersed in ethyl acetate (50 mL), washed successively with HCl (1N), water, and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V PE : V EA =3 : 1), to obtain compound 2f (118mg, 19%, orange solid).
Yield:118mg,19％,orange solid；Rf＝0.369(Petroluem ether:EtOAc＝3:1).M.p 87-89℃.1H NMR(400MHz,CDCl3)δ(ppm):7.60(d,J＝8.8Hz,2H,Ar-H),7.39(s,1H),6.96(d,J＝8.8Hz,2H,Ar-H),5.64(s,1H,12-H),4.14-3.98(m,4H,2×OCH2),3.22(dd,J＝10.7,5.3Hz,1H,3-H),2.78(d,J＝13.5Hz,1H,18-H),2.34(s,1H,9-H),2.17-0.64(m,33H),1.16-1.10(m,9H,3×CH3),1.00(s,3H,CH3),0.80(s,6H,2×CH3).13C NMR(100MHz,CDCl3)δ(ppm):215.2,200.3,176.6,173.3,169.4,162.7,134.6,128.7,128.6,124.0,115.6,78.8,68.5,64.6,61.9,55.1,48.5,45.5,44.1,43.3,41.2,39.2,37.9,37.2,32.9,31.9,31.3,29.3,29.2,29.1,28.7,28.5,28.2,27.4,26.6,26.5,26.0,26.0,23.5,18.8,17.6,16.5,15.7.HRMS(APCl)m/z:[M+H]+calcd forC47H67O5S3,807.4151；found 807.4118.Yield: 118mg, 19%, orange solid; Rf = 0.369 (Petroluem ether:EtOAc = 3:1). Mp 87-89°C. 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.60 (d, J =8.8Hz,2H,Ar-H),7.39(s,1H),6.96(d,J=8.8Hz,2H,Ar-H),5.64(s,1H,12-H),4.14-3.98(m ,4H,2×OCH 2 ),3.22(dd,J=10.7,5.3Hz,1H,3-H),2.78(d,J=13.5Hz,1H,18-H),2.34(s,1H,9 13 _ _ _ C NMR (100MHz, CDCl 3 ) δ (ppm): 215.2, 200.3, 176.6, 173.3, 169.4, 162.7, 134.6, 128.7, 128.6, 124.0, 115.6, 78.8, 68.5, 64.6, 61.9, 55.1, 48.5, 45.5, 44.1 . (APCl) m/z: [M+H] + calcd for C 47 H 67 O 5 S 3 , 807.4151; found 807.4118.
实施例11：化合物2g的合成Embodiment 11: the synthesis of compound 2g
将化合物1c(250mg,0.39mmol)溶于DMF(5mL)，加入TBZ(60.35mg,0.39mmol)、K2CO3(28mg,0.2mmol)、KI(6.30mg,0.04mmol)，35℃反应12h。残余物分散在乙酸乙酯(50mL)，依次用HCl(1N)、水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析分离(VPE:VEA＝3:1)，得化合物2g(91mg,32％,浅黄色固体)。Dissolve compound 1c (250mg, 0.39mmol) in DMF (5mL), add TBZ (60.35mg, 0.39mmol), K 2 CO 3 (28mg, 0.2mmol), KI (6.30mg, 0.04mmol), and react at 35°C for 12h . The residue was dispersed in ethyl acetate (50 mL), washed successively with HCl (1N), water, and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V PE : V EA =3 :1), compound 2g (91mg, 32%, light yellow solid) was obtained.
Yield:91mg,32％,yellow solid；Rf＝0.267(Petroluem ether:EtOAc＝3:1).M.p 119-120℃.1H NMR(500MHz,DMSO-d6)δ(ppm):9.30(s,1H,NH)，8.23(s,1H,NH),7.48(d,J＝8.8Hz,2H,Ar-H),6.99(d,J＝8.9Hz,2H,Ar-H),5.40(s,1H,12-H),4.02–3.96(m,4H,2×OCH2),2.98(d,J＝4.5Hz,1H,3-H),2.55(d,J＝13.2Hz,1H,18-H),2.30(s,1H),2.18–0.63(m,28H),1.08,0.89and 0.72(3s,each 3H,3×CH3,1.00and 0.67(2s,each 6H,4×CH3).13C NMR(125MHz,DMSO-d6)δ(ppm):199.1,191.7,175.9,169.5,161.6,134.2,126.4,120.9,115.0,76.6,67.8,63.9,61.2,54.1,48.1,44.9,43.6,42.9,37.4,36.7,32.1,31.6,30.4,29.1,28.7,28.6,28.5,28.32,28.28,28.2,27.8,27.0,26.1,25.8,25.6,25.4,23.0,22.2,18.4,17.2,16.2,16.1.HRMS(ESI)m/z:[M+Na]+calcd for C43H64NO5S,706.4505；found 706.4500.Yield: 91mg, 32%, yellow solid; R f = 0.267 (Petroluem ether: EtOAc = 3: 1). Mp 119-120 ° C. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 9.30 (s, 1H, NH), 8.23(s, 1H, NH), 7.48(d, J=8.8Hz, 2H, Ar-H), 6.99(d, J=8.9Hz, 2H, Ar-H), 5.40(s, 1H,12-H), 4.02–3.96(m,4H,2×OCH 2 ),2.98(d,J=4.5Hz,1H,3-H),2.55(d,J=13.2Hz,1H,18- H),2.30(s,1H),2.18–0.63(m,28H),1.08,0.89and 0.72(3s,each 3H,3×CH 3 ,1.00and 0.67(2s,each 6H,4×CH 3 ). 13 C NMR (125MHz, DMSO-d6) δ (ppm): 199.1, 191.7, 175.9, 169.5, 161.6, 134.2, 126.4, 120.9, 115.0, 76.6, 67.8, 63.9, 61.2, 54.1, 48.1, 44.9, 43.6, 42.9 HR (ESI) m/z: [M+Na] + calcd for C 43 H 64 NO 5 S, 706.4505; found 706.4500.
实施例12：化合物2h的合成Embodiment 12: the synthesis of compound 2h
将化合物1d(250mg,0.38mmol)溶于DMF(5mL)，加入TBZ(57.80mg,0.38mmol)、K2CO3(28mg,0.20mmol)、KI(6.30mg,0.04mmol)，35℃反应12h。残余物分散在乙酸乙酯(50mL)，依次用HCl(1N)、水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析分离(VPE:VEA＝3:1)，得化合物2h(107mg,39％,浅黄色固体)。Dissolve compound 1d (250mg, 0.38mmol) in DMF (5mL), add TBZ (57.80mg, 0.38mmol), K 2 CO 3 (28mg, 0.20mmol), KI (6.30mg, 0.04mmol), and react at 35°C for 12h . The residue was dispersed in ethyl acetate (50 mL), washed successively with HCl (1N), water, and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V PE : V EA =3 :1), to obtain compound 2h (107mg, 39%, pale yellow solid).
Yield:107mg,39％,yellow solid；Rf＝0.206(Petroluem ether:EtOAc＝3:1).M.p 117-119℃.1H NMR(500MHz,DMSO-d6)δ(ppm):9.63(s,1H,NH),9.31(s,1H,NH),7.94(d,J＝8.9Hz,2H,Ar-H),6.91(d,J＝8.9Hz,2H,Ar-H),5.42(s,1H,12-H),4.01(m,4H,2×OCH2),3.01(dd,J＝11.4,4.4Hz,1H,3-H),2.58(s,1H,18-H),2.31(s,1H),2.15-0.64(m,32H),1.09,0.90and 0.73(3s,each 3H,3×CH3),1.02and 0.68(2s,each 6H,4×CH3).13CNMR(125MHz,DMSO-d6)δ(ppm):199.0,198.5,175.8,169.4,161.4,131.1,129.5,127.4,113.4,76.6,67.7,63.9,61.2,59.8,54.1,48.1,44.9,43.6,42.9,37.4,36.7,32.1,31.5,30.4,28.5,28.2,27.8,27.0,26.1,25.8,25.4,25.2,23.0,20.8,18.4,16.2,16.0,14.4.HRMS(ESI)m/z:[M+Na]+calcd forC45H68NO5S,734.4818；found 734.4816.Yield: 107mg, 39%, yellow solid; Rf = 0.206 (Petroluem ether:EtOAc = 3:1).Mp 117-119°C. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 9.63 (s, 1H,NH),9.31(s,1H,NH),7.94(d,J=8.9Hz,2H,Ar-H),6.91(d,J=8.9Hz,2H,Ar-H),5.42(s, 1H,12-H), 4.01(m,4H,2×OCH 2 ),3.01(dd,J=11.4,4.4Hz,1H,3-H),2.58(s,1H,18-H),2.31( s,1H),2.15-0.64(m,32H),1.09,0.90and 0.73(3s,each 3H,3×CH 3 ),1.02and 0.68(2s,each 6H,4×CH 3 ). 13 CNMR(125MHz ,DMSO-d6)δ(ppm): 199.0, 198.5, 175.8, 169.4, 161.4, 131.1, 129.5, 127.4, 113.4, 76.6, 67.7, 63.9, 61.2, 59.8, 54.1, 48.1, 44.9, 43.6, 42.9, 37.4, 36.7, 32.1, 31.5, 30.4, 28.5, 28.2, 27.8, 27.0, 26.1, 25.8, 25.4, 25.2, 23.0, 20.8, 18.4, 16.2, 16.0, 14.4. HRMS (ESI) m/z: [M+Na] + calcd for C 45 H 68 NO 5 S, 734.4818; found 734.4816.
实施例13：化合物2a的合成Embodiment 13: the synthesis of compound 2a
重复实施例5，不同的是：用甲苯替代DMF，用碳酸铯替代K2CO3，且将温度改为40℃反应12h。Example 5 was repeated, except that toluene was used instead of DMF, cesium carbonate was used instead of K 2 CO 3 , and the temperature was changed to 40° C. for 12 h.
所得产物(228mg,75％,淡黄色固体)经过核磁鉴定为化合物2a，其结构式如下所示：The obtained product (228 mg, 75%, pale yellow solid) was identified as compound 2a by NMR, and its structural formula is as follows:
实施例14：化合物2b的合成Embodiment 14: the synthesis of compound 2b
重复实施例6，不同的是：用吡啶替代DMF，用碳酸氢钾替代K2CO3，且加入相当于化合物1b物质的量0.5倍的催化剂KI。Example 6 was repeated except that pyridine was used instead of DMF, potassium bicarbonate was used instead of K 2 CO 3 , and catalyst KI was added 0.5 times the amount of compound 1b.
所得产物(166mg,55％,淡黄色固体)经过核磁鉴定为化合物2b，其结构式如下所示：The obtained product (166mg, 55%, pale yellow solid) was identified as compound 2b by NMR, and its structural formula is as follows:
实施例15：化合物2e的合成Embodiment 15: the synthesis of compound 2e
重复实施例9，不同的是：用甲苯替代DMF，用碳酸钠替代K2CO3，且不加入催化剂KI，将残余物分散于二氯甲烷中。Example 9 was repeated except that DMF was replaced by toluene, K2CO3 was replaced by sodium carbonate, and catalyst KI was not added, and the residue was dispersed in dichloromethane.
所得产物(72mg,12％,橙色固体)经过核磁鉴定为化合物2e，其结构式如下所示：The obtained product (72mg, 12%, orange solid) was identified as compound 2e by NMR, and its structural formula is as follows:
实施例16：化合物2f的合成Embodiment 16: the synthesis of compound 2f
重复实施例10，不同的是：用用甲苯和DMF的组合物(由甲苯和DMF按1：1的体积比组成)替代DMF，用三乙胺替代K2CO3，且不加入催化剂KI，将残余物分散于乙醚中。Repeat Example 10, the difference is: replace DMF with a composition of toluene and DMF (made up of toluene and DMF in a volume ratio of 1:1), replace K 2 CO 3 with triethylamine, and do not add catalyst KI, The residue was dispersed in ether.
所得产物(62mg,10％,橙色固体)经过核磁鉴定为化合物2f，其结构式如下所示：The obtained product (62mg, 10%, orange solid) was identified as compound 2f by NMR, and its structural formula is as follows:
实施例16：化合物2h的合成Embodiment 16: the synthesis of compound 2h
重复实施例12，不同的是：用吡啶和甲苯的组合物(由甲吡啶和甲苯按1：5的体积比组成)替代DMF，用碳酸氢钠替代K2CO3，且不加入催化剂KI。Example 12 was repeated except that DMF was replaced by a composition of pyridine and toluene (consisting of picoline and toluene at a volume ratio of 1:5), K 2 CO 3 was replaced by sodium bicarbonate, and catalyst KI was not added.
所得产物(49mg,18％,浅黄色固体)经过核磁鉴定为化合物2h，其结构式如下所示：The obtained product (49 mg, 18%, light yellow solid) was identified as compound 2h by NMR, and its structural formula is as follows:
申请人对本发明所述化合物2a～2h对人肝癌肿瘤细胞株及慢性骨髓性白血病细胞的增殖抑制活性进行了实验：The applicant tested the proliferation inhibitory activity of compounds 2a-2h of the present invention on human liver cancer tumor cell lines and chronic myelogenous leukemia cells:
1、细胞株与细胞培养1. Cell lines and cell culture
本实验选用人肝癌细胞BEL-7402、慢性骨髓性白血病细胞K562以及人正常肝细胞L-O2等3种人类细胞株。In this experiment, three human cell lines including human liver cancer cell BEL-7402, chronic myelogenous leukemia cell K562 and normal human liver cell L-O2 were selected.
所有细胞株均培养在含10wt％小牛血、100U/mL青霉素、100U/mL链霉素的RPMI-1640培养液内，置37℃含体积浓度5％CO2孵箱中培养。All cell lines were cultured in RPMI-1640 medium containing 10wt% calf blood, 100U/mL penicillin, and 100U/mL streptomycin in an incubator at 37°C with a volume concentration of 5% CO 2 .
2、待测化合物的配制2. Preparation of test compounds
所用的受试药物的纯度≥95％，将其DMSO储液用生理缓冲液稀释后配制成200μmol/L的终溶液，其中助溶剂DMSO的终浓度≤1％，测试该浓度下化合物对各种肿瘤细胞生长的抑制程度。The purity of the test drug used is ≥95%, and its DMSO stock solution is diluted with physiological buffer solution to prepare a final solution of 200 μmol/L, wherein the final concentration of co-solvent DMSO is ≤1%, and the compound is tested at this concentration for various Inhibition of tumor cell growth.
3、细胞生长抑制实验(MTT法)3. Cell growth inhibition test (MTT method)
(1)取对数生长期的肿瘤细胞，经胰蛋白酶消化后，用含10％小牛血清的培养液配制成浓度为5000个/mL的细胞悬液，以每孔190μL接种于96孔培养板中，使待测细胞密度至1000～10000孔(边缘孔用无菌PBS填充)；(1) Take the tumor cells in the logarithmic growth phase, digest them with trypsin, prepare a cell suspension with a concentration of 5000 cells/mL with a culture medium containing 10% calf serum, inoculate 190 μL per well in 96-well culture In the plate, make the cell density to be tested to 1000-10000 wells (the edge wells are filled with sterile PBS);
(2)5％CO2，37℃孵育24h，至细胞单层铺满孔底，每孔加入一定浓度梯度的药物10μL，每个浓度梯度设4个复孔；(2) 5% CO 2 , incubate at 37°C for 24 hours, until the cell monolayer covers the bottom of the well, add 10 μL of drug with a certain concentration gradient to each well, and set 4 replicate wells for each concentration gradient;
(3)5％CO2，37℃孵育48小时，倒置显微镜下观察；(3) 5% CO 2 , incubate at 37°C for 48 hours, observe under an inverted microscope;
(4)每孔加入10μL的MTT溶液(5mg/mL PBS，即0.5％MTT)，继续培养4h；(4) Add 10 μL of MTT solution (5 mg/mL PBS, ie 0.5% MTT) to each well, and continue to incubate for 4 h;
(5)终止培养，小心吸去孔内培养液，每孔加入150μL的DMSO充分溶解甲瓒沉淀，振荡器混匀后，在酶标仪用波长为570nm，参比波长为450nm测定各孔的光密度值；(5) Terminate the culture, carefully suck off the culture medium in the wells, add 150 μL of DMSO to each well to fully dissolve the formazan precipitate, mix well with a shaker, and measure the concentration of each well in a microplate reader with a wavelength of 570 nm and a reference wavelength of 450 nm. optical density value;
(6)同时设置调零孔(培养基、MTT、DMSO)，对照孔(细胞、相同浓度的药物溶解介质、培养液、MTT、DMSO)。(6) At the same time, set zero adjustment wells (medium, MTT, DMSO) and control wells (cells, drug dissolution medium with the same concentration, culture medium, MTT, DMSO).
(7)根据测得的光密度值(OD值)，来判断活细胞数量，OD值越大，细胞活性越强。利用公式：(7) According to the measured optical density value (OD value), the number of living cells is judged. The larger the OD value, the stronger the cell activity. Use the formula:
计算化合物对各细胞株生长的抑制率，其结果如以下表1所示。The inhibition rate of the compound on the growth of each cell line was calculated, and the results are shown in Table 1 below.
表1：各化合物对不同细胞株的IC50值(μM)Table 1: IC 50 values (μM) of each compound against different cell lines
注：实验数据为3次实验的平均值，Nd表示受试化合物对此细胞检测不到抑制活性。Note: The experimental data is the average value of 3 experiments, and Nd means that the test compound has no detectable inhibitory activity on this cell.
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